Crystal structures of trimeric HIV envelope with entry inhibitors BMS-378806 and BMS-626529

Abstract

The HIV-1-envelope (Env) spike is a conformational machine that transitions between prefusion (closed, CD4-bound, CCR5-bound) and postfusion states to facilitate HIV-1 entry. Although the prefusion-closed conformation is a potential target for inhibition, development of small molecule leads has been stymied by difficulties in obtaining structural information. Here, we report crystal structures at 3.8-Å resolution of HIV-1-Env trimer with BMS-378806 and its derivative, BMS-626529, for which a prodrug version is currently in Phase III-clinical trials. Both lead candidates recognized an induced-binding pocket, which was mostly excluded from solvent and comprised of Env elements from a conserved helix and the β20-21-hairpin. In both structures, the β20-21-region assumed a conformation distinct from prefusion-closed and CD4-bound states. Together with biophysical and antigenicity characterizations, the structures illuminate the allosteric and competitive mechanisms whereby these small-molecule leads inhibit CD4–induced structural changes in Env.

Structural survey of HIV-1-neutralizing antibodies targeting Env trimer delineates epitope categories and suggests vaccine templates

“…In some cases, multiple runs were averaged. The values used here differed slightly, generally within 2 fold of previous median IC 50 , from previously reported values in references (5,7,11,22,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40).…”

“…For the PGT121 class, we chose 8 antibody 10-1074 (14); for the VRC01 class, we chose antibody N6 (24); and for the 8ANC131 class we chose antibody CH235.12 (25). Notably, the newly measured median neutralization IC50 generally differed by less than 2 fold from prior reported values (5,7,11,22,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40), with the breadth for all 20 classes averaging 56.7%, with an average geometric mean IC 50 of 0.27 μ g/ml.…”

Disruption of the HIV-1 Envelope allosteric network blocks CD4-induced rearrangements

“…The small molecule BMS-626529 is an attachment inhibitor that stabilizes the Env SOSIP in its prefusion closed state preventing CD4 binding and triggering. 32,33 BMS-626529 neutralizes Env pseudoviuruses with nanomolar (nM) IC50, and has shown efficacy in blocking HIV-1 infection in vitro and in vivo . 32 Further, BMS-626529 is known to stabilize membrane Env gp160 in its closed, functional state 33 , which is an important target in Env immunogen design efforts.…”

“…32,33 BMS-626529 neutralizes Env pseudoviuruses with nanomolar (nM) IC50, and has shown efficacy in blocking HIV-1 infection in vitro and in vivo . 32 Further, BMS-626529 is known to stabilize membrane Env gp160 in its closed, functional state 33 , which is an important target in Env immunogen design efforts. Based upon the known allosteric control elements in the Env 27,28,30 and atomic level details of the binding site of the BMS-626529 inhibitor 33 , we designed mutations that disrupted the Env allosteric network and rendered it unresponsive to CD4-induced structural rearrangements.…”

“…32 Further, BMS-626529 is known to stabilize membrane Env gp160 in its closed, functional state 33 , which is an important target in Env immunogen design efforts. Based upon the known allosteric control elements in the Env 27,28,30 and atomic level details of the binding site of the BMS-626529 inhibitor 33 , we designed mutations that disrupted the Env allosteric network and rendered it unresponsive to CD4-induced structural rearrangements. Structure determination via single particle cryo-EM revealed key details regarding how allosteric elements downstream from the gp120-CD4 contact control transitions of the trimer between the Env closed and open states.…”